WO2016094764A1 - Les peptides dérivés de la collagénase activent la régénération tissulaire et la cicatrisation des plaies - Google Patents

Les peptides dérivés de la collagénase activent la régénération tissulaire et la cicatrisation des plaies Download PDF

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Publication number
WO2016094764A1
WO2016094764A1 PCT/US2015/065181 US2015065181W WO2016094764A1 WO 2016094764 A1 WO2016094764 A1 WO 2016094764A1 US 2015065181 W US2015065181 W US 2015065181W WO 2016094764 A1 WO2016094764 A1 WO 2016094764A1
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peptides
peptide
wound
wound healing
isolated
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PCT/US2015/065181
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English (en)
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Ira M. Herman
Tatiana DEMIDOVA-RICE
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Tufts University
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Priority to JP2017531329A priority Critical patent/JP2018502566A/ja
Priority to US15/534,140 priority patent/US10485846B2/en
Priority to EP15868322.7A priority patent/EP3229821B1/fr
Priority to AU2015360399A priority patent/AU2015360399A1/en
Priority to CA3007181A priority patent/CA3007181C/fr
Publication of WO2016094764A1 publication Critical patent/WO2016094764A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/4886—Metalloendopeptidases (3.4.24), e.g. collagenase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/472—Complement proteins, e.g. anaphylatoxin, C3a, C5a
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/485—Epidermal growth factor [EGF], i.e. urogastrone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6489—Metalloendopeptidases (3.4.24)
    • C12N9/6491—Matrix metalloproteases [MMP's], e.g. interstitial collagenase (3.4.24.7); Stromelysins (3.4.24.17; 3.2.1.22); Matrilysin (3.4.24.23)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/24—Metalloendopeptidases (3.4.24)
    • C12Y304/24007—Interstitial collagenase (3.4.24.7), i.e. matrix metalloprotease 1 or MMP1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/50—Fusion polypeptide containing protease site

Definitions

  • Wound healing is a complex, highly-coordinated process that begins and ends with tissue remodeling.
  • the extracellular matrix and its associated growth regulatory substances play a pivotal role in dynamically and reciprocally regulating the cellular response and wound healing.
  • the enzymes and structural macromolecules of the extracellular matrix cooperate with cytokines and growth factors, yielding a dynamic that orchestrates healing (1-7).
  • Re- epithelialization involves the migration and proliferation of epithelial tissue, primarily keratinocytes.
  • Angiogenesis is the growth of new blood vessels from pre-existing conduits, and is regulated by a panoply of soluble cytokines including growth factor polypeptides, as well as cell-cell and cell-matrix interactions.
  • Chronic wounds exhibit a different healing profile from normal acute wounds in that they generally remain in an inflamed state for protracted periods of time. Non-healing wounds can most commonly be observed amongst people with diabetes, venous stasis disease, and in those patients who are immobilized.
  • wound healing peptides are resistant to the degrading and compromising action of the "hostile" environment, which typifies non-healing wounds.
  • Prior attempts to develop advanced protein-based wound healing therapeutics have largely failed because the wound bed's robust protease profile degrades any bioactive protein entity that is delivered.
  • bioactive wound healing peptides that are resistant to protease action are highly beneficial since the peptides promote tissue remodeling, angiogenesis and epithelialization despite the elevated protease profile present within the wounds.
  • activation of healing help to "re-equilibrate" the wound bed, thus potentially up-regulating protease inhibitors, down-regulating host proteases or both.
  • an isolated peptide that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-19.
  • the peptide includes less than 100, 95, 90, 85, 80 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25 or 20 amino acids.
  • an isolated peptide includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-19, wherein the peptide does not include a full-length protein from which the peptide was derived.
  • the peptide includes not more than 50, 45, 40, 35, 30, 25 or 20 contiguous amino acid residues of the protein from which the peptide was derived.
  • the peptide consists essentially of an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-19.
  • a combinatorial peptide includes an isolated peptide disclosed herein conjugated or fused to a second peptide or polypeptide.
  • a composition or article of manufacture includes one or more of the isolated peptides disclosed herein, or one or more of the combinatorial peptides disclosed herein, and a carrier or excipient.
  • the carrier or excipient is a pharmaceutically acceptable carrier or excipient.
  • the one or more of the isolated peptides or one or more of the combinatorial peptides include protease cleavage sites; optionally the protease cleavage sites are different in different peptides or combinatorial peptides.
  • the one or more isolated peptides or one or more combinatorial peptides are anchored to a scaffold, which optionally is a bioerodible and non-immunogenic scaffold.
  • methods are provided to promote wound healing in a subject in need thereof.
  • the methods include administering to the subject an effective amount of one or more of the isolated peptides disclosed herein, one or more of the combinatorial peptides disclosed herein, or the composition or article of manufacture disclosed herein.
  • the peptide consists essentially of an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-19.
  • the peptide is administered in an amount effective to enhance the rate of migration of keratinocytes or endothelial cells, or a combination of keratinocytes and endothelial cells, towards a wound edge.
  • the administration of the peptide results in an increase in the re- epithelialization of the wound.
  • the administration of the peptide results in an increase in angiogenesis in or near the wound.
  • the peptide is administered at a wound site.
  • the wound is a thermal, chronic, acute or surgical wound.
  • the methods further include administering to the subject a second agent.
  • the second agent is a polypeptide.
  • the second agent is a growth factor, cytokine, or enzyme. In some embodiments, the second agent is a growth factor, cytokine, or enzyme.
  • the second agent is a non-human collagenase.
  • the non-human collagenase is bacterial collagenase.
  • the subject is a mammalian subject. In some embodiments, the mammalian subject is a human.
  • Figures 1A-1B show that SANTYL® collagenase API releases unique fragments from human endothelial ECM and matrices derived from human fibroblasts (shown).
  • the matrices were prepared and processed as described in references 5,8-10. Samples derived from buffer insoluble and soluble ECM fractions as well as self-degraded enzymes were loaded into SDS-containing PAGE and subjected to electrophoresis. Unique protein bands present within soluble fractions of digested matrices (arrowheads) were analyzed by mass spectrometry.
  • Figure 2 shows that peptides derived from human endothelial ECM stimulate proliferation of human endothelial cells.
  • Human microvascular endothelial cells were plated at low density in multi-well plates and treated with 100 nM peptides every other day. At day 5 post-plating the cells were counted using a coulter counter. Cell proliferation relative to control is shown, statistical significance (p ⁇ 0.05).
  • Figures 3A-3B show that peptides derived from human endothelial ECM stimulate proliferation of adult human keratinocytes in dose-dependent manner.
  • Adult human keratinocytes were plated at low density in multi-well plates and treated with 10 nM peptides (Figure 3A) or 1-100 nM peptides ( Figure 3B) every other day. At day 7 post-plating the cells were counted using a coulter counter. Cell proliferation relative to control ( Figure 3A) or absolute cell number grown ( Figure 3B) are shown, statistical significance (p ⁇ 0.05).
  • FIG. 4 shows that peptides derived from ECM degraded by bacterial collagenase stimulate angiogenesis in vitro.
  • ECM-derived peptides were dissolved in growth factor- reduced Matrigel at 100 nM, the matrix was allowed to polymerize, human microvascular endothelial cells were plated either in control low serum containing media or media containing 100 nM peptides. Representative images of cells treated with endothelial ECM- derived peptides are shown.
  • FIG. 5 shows that ECM-derived peptides stimulate epithelial wound healing in vitro.
  • Adult human keratinocytes were plated into glass-bottom well plates at high density. Scratch wounds were made in the cell monolayer 24h post-plating. The peptides dissolved in keratinocyte growth media (10 nM) were applied immediately after wounding. Wound closure was monitored at 0, 1, 3 and 5 hours post- injury. Dashed line outlines the wounds. Representative images of wounds treated with TSN2 and TSN6 are shown.
  • Figure 6 shows the experimental design for in vivo testing of peptides.
  • Balb/c mice were pre-treated with cyclophosphamide at 150 mg/kg 3 days prior to injury and with 100 mg/kg cyclophosphamide 1 day before injury.
  • Cranial cutaneous wounds were created using 4 mm punch biopsy tool and immediately covered with adherent transparent dressing
  • TEGADERMTM Laboratory Animal Medicine
  • Figures 7A-7L show that ECM-derived peptides stimulate cellular responses to injury in a mouse model of impaired healing. Cranial cutaneous wounds were created in
  • CMC carboxymethyl cellulose
  • FIG 8 shows that ECM-derived peptides stimulate wound healing in mice. Wounds were created, treated as described in Figure 6 and scored in a blind manner according to the grading described in Table 2. * indicates statistical significance of findings (p ⁇ 0.05).
  • FIG. 9 shows ECM-derived peptides stimulate wound epithelialization in mice. Wounds were created and treated as described in Figure 1. Wound epithelialization was measured at day 6 post wounding. ** indicate statistical significance of findings (p ⁇ 0.05). Treatments from left to right: control; TSN6, 0.1 mg/ml; TSN6, 1 mg/ml; TSN18, 0.1 mg/ml; TSN18, 1 mg/ml; PK coUagenase.
  • Wound healing is predicated upon the migration and proliferation of cells at or near the wound edge and the recruitment of new or pre-existing blood vessels to the wound site.
  • wound healing peptides that stimulate keratinocyte and/or endothelial cell motility and/or proliferation.
  • kits and articles of manufacture comprising one or more of the wound healing peptides.
  • ECM extracellular matrices
  • API active pharmaceutical ingredient
  • a bacterial coUagenase isolated from a Clostridial bacterium results in the liberation of several peptides not known to be found as such in nature. These peptides are believed not formed by the treatment of ECM with a human coUagenase.
  • These peptides can be isolated from digested ECM, produced in cells by expression of recombinant nucleic acids encoding the peptide(s), or synthesized using conventional peptide synthesis methods well-known in the art.
  • combinatorial peptides can be generated by combining all or portions of two or more wound healing peptides. Exemplary peptides and combinatorial peptides (SEQ ID NOs: 1-19) are provided in Table 1.
  • the methods, kits, and articles of manufacture provided herein can include more than one peptide, wherein at least one of the peptides is selected from SEQ ID NOs: 1-19, or peptides that comprise or consist essentially of SEQ ID NOs: 1-19.
  • a wound healing peptide includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-19, and the peptide comprises 100, 95, 90, 85, 80 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, or fewer amino acids.
  • a wound healing peptide can comprise 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 amino acids.
  • a wound healing peptide includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-19, and the peptide does not comprise a full-length protein from which the peptide was derived.
  • the peptide comprises not more than 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9 or 8 contiguous amino acid residues of the protein from which the peptide was derived.
  • Certain wound healing peptides are combinatorial peptides which are combinations of peptides that include at least one of the peptides disclosed herein. Such peptides are not naturally occurring and cannot be produced by in situ cleavage. Instead, combinatorial peptides are produced by chemical synthesis or by expression of a recombinant nucleic acid that encodes the combinatorial peptide, such as a protein expression vector as described elsewhere herein.
  • Non-limiting examples of combinatorial peptides include peptides that comprise one or more of SEQ ID NOs: 1-8, 11, 12, 14-17.
  • peptides TSN9, TSN10, TSN13, TSN18 and TSN19 are examples of combinatorial peptides; see Table 1.
  • the peptides can be linked consecutively, with the C-terminal end of one peptide linked via peptide bond to the N-terminal amino acid of another peptide.
  • the peptides are linked by one or more linkers that can include one or more amino acids that are not part of the peptides linked in the combinatorial peptide.
  • wound healing peptides have been demonstrated herein, using well characterized in vitro and in vivo methods and wound healing assays. The results of the assays are described herein.
  • the wound healing peptides provided herein are also useful in the promotion of capillary morphogenesis and to induce endothelial cell proliferation.
  • Cells types that can be affected by the wound healing peptides provided herein include keratinocytes, endothelial cells such as microvascular endothelial cells, fibroblasts and pericytes.
  • the wound healing peptides provided herein also can be used in conjunction with a bio-compatible wound product.
  • the wound product can be, for example, a biomaterial derived from mammalian tissue.
  • the wound product can be provided in purified or unpurified form.
  • the wound product can be modified by the addition of one or more compounds that act as functional crosslinkers (e.g., l-Ethyl-3-[3- dimethylaminopropyl]carbodiimide hydrochloride (EDC) or N-hydroxysulfosuccinimide (sulfo-NHS)).
  • EDC l-Ethyl-3-[3- dimethylaminopropyl]carbodiimide hydrochloride
  • sulfo-NHS N-hydroxysulfosuccinimide
  • a commercially-available wound product e.g., OASIS® Wound Matrix, distributed by Smith & Nephew, Fort Worth, Tex.
  • OASIS® Wound Matrix distributed by Smith & Nephew, Fort Worth, Tex.
  • a wound healing peptide in the presence or absence of one or more functional crosslinkers.
  • peptides can be engineered to possess cleavage sites so that they can be quantitatively released, unhindered or without loss of bioactivity, from the scaffold to act in a temporally and spatially specific manner.
  • anchoring on a scaffold would afford release of an angiogenically-active bioactive peptide before the controlled release of a bioactive peptide that promotes epithelialization.
  • blood vessel formation would be activated before epithelialization so that nutrients could be locally delivered in support of the epithelialization process by the angiogenic peptide activators preceding the epithelialization activators.
  • nucleic acid molecules that encode the disclosed wound healing peptides and combinatorial peptides.
  • the sequence of such nucleic acids is determined according to the standard genetic code in which one or more three-nucleotide codons encode an amino acid of the wound healing peptides or combinatorial peptides.
  • kits for the treatment of wounds in a subject containing one or more wound healing peptides.
  • the kit includes instructions for using the peptide to treat a wound or wounds in the subject.
  • the kit includes one or more other materials that enhance wound healing.
  • the kit can contain a bio-compatible wound product, a growth factor, a cytokine, or an enzyme.
  • Suitable subjects include, for example, a patient with having a wound.
  • the patient has diabetes.
  • the subject is a burn patient.
  • the wound is a chronic wound.
  • a non-human (e.g., bacterial) collagenase may also be included in the kit. Articles of manufacture are also provided.
  • an article of manufacture includes one or more wound healing peptides (e.g., one or more peptides including the amino acid sequence of any one or more of SEQ ID NOs: 1-19) and, optionally, one or more growth factors, cytokines, or enzymes.
  • the article is suitable for use in a medical treatment of a mammalian subject.
  • the article can be or include a skin or tissue equivalent.
  • the article comprises one or more growth factors, cytokines, or enzymes.
  • a non-human (e.g., bacterial) collagenase may also be included in or on the article.
  • Suitable absorbent products are capable of absorbing a wound fluid when applied at a wound site.
  • the absorbent product comprises a structure that is capable of absorbing liquid and a wound healing peptide.
  • Exemplary structures include, for example, bandages, gauzes, wound or sore dressings, dermal patches and adhesive tapes.
  • the term "liquid absorbent structure" refers broadly to any material applied to a wound for protection, absorbance, drainage, etc. Thus, adsorbent and absorbent materials are specifically contemplated as a solid support.
  • films e.g., polyurethane films
  • hydrocolloids hydrophilic colloidal particles bound to polyurethane foam
  • hydrogels cross-linked polymers containing about at least 60% water
  • foams hydrophilic or hydrophobic
  • calcium alginates nonwoven composites of fibers from calcium alginate
  • cellophane cellulose with a plasticizer
  • liquid absorbent structures where one or more wound healing peptides are impregnated within or attached (covalently or otherwise) to the surface of the structure.
  • Wound healing peptides described herein can be produced synthetically, or by proteolytic digestion of suitable biological materials by one or more enzymes such as collagenase.
  • nucleotide sequences encoding wound healing peptides can be introduced into a protein expression vector and produced in a suitable host organism (e.g., bacteria, yeast, insect cells, etc.). Regardless of the origin or method of producing the peptides, following production, the peptides can be isolated and optionally purified.
  • Peptides can be engineered to possess known wound protease cleavage sites to release a bioactive wound healing peptide or an angiogenesis-activating peptide locally with time and space control. Modified Wound Healing Peptides
  • wound healing peptides can be modified as is well-known in the art.
  • the wound healing peptides are modified by the addition of one or more functional groups such as phosphate, acetate, or various lipids and carbohydrates.
  • Wound healing peptides can also exist as peptide derivatives.
  • the term "peptide derivative" refers to compound having an imino group (-NH-), and more particularly, a peptide bond.
  • Peptides may be regarded as substituted amides.
  • the peptide bond shows a high degree of resonance stabilization.
  • Protecting groups are those groups that prevent undesirable reactions (such as proteolysis) involving unprotected functional groups.
  • the protecting group is an acyl or an amide.
  • the acyl is acetate.
  • another functional groups such as phosphate, acetate, or various
  • the protecting group is a benzyl group. In another embodiment, the protecting group is a benzoyl group.
  • the technology provided herein includes combinations of such protecting groups.
  • Peptide or “polypeptide” refers to a polymer in which the monomers are alpha amino acids joined together through amide bonds. Peptides are two or often more amino acid monomers long.
  • Amino acid residues in peptides are abbreviated as follows:
  • Phenylalanine is Phe or F; Leucine is Leu or L; Isoleucine is He or I; Methionine is Met or M; Valine is Val or V; Serine is Ser or S; Proline is Pro or P; Threonine is Thr or T; Alanine is Ala or A; Tyrosine is Tyr or Y; Histidine is His or H; Glutamine is Gin or Q; Asparagine is Asn or N; Lysine is Lys or K; Aspartic Acid is Asp or D; Glutamic Acid is Glu or E;
  • Cysteine is Cys or C; Tryptophan is Trp or W; Arginine is Arg or R; and Glycine is Gly or G.
  • Stereoisomers e.g., D-amino acids
  • unnatural amino acids such as a,a-disubstituted amino acids, N-alkyl amino acids, lactic acid, and other unconventional amino acids may also be suitable components for compounds of the technology provided herein.
  • unconventional amino acids include: .beta.
  • -alanine 1-naphthylalanine, 2-naphthylalanine, 3-pyridylalanine, 4-hydroxyproline, O-phosphoserine, N-acetylserine, N-formylmethionine, 3-methylhistidine, 5-hydroxylysine, nor-leucine, and other similar amino acids and imino acids (e.g., 4-hydroxyproline).
  • polypeptides can be added on for the purpose of purifying or identifying or purifying the wound healing peptides.
  • Protein tags make it possible, for example, for the polypeptides to be adsorbed, with high affinity, to a matrix, and for the matrix then to be washed stringently with suitable buffers without the complex being eluted to any significant extent, and for the adsorbed complex subsequently to be eluted selectively.
  • protein tags which are known to the skilled person are a (His)6 tag, a Myc tag, a FLAG tag, a haemagglutinin tag, a glutathione transferase (GST) tag, an intein having an affinity chitin-binding tag or maltose-binding protein (MBP) tag.
  • GST glutathione transferase
  • MBP maltose-binding protein
  • biological materials include, without being limited to, growth factors, cytokines, enzymes, and ECM components.
  • collagenase treatment of the sub-endothelial extracellular matrix can be used in combination with wound healing peptide treatment to accelerates endothelial migration and proliferation to a level greater than the inductive influence of collagenase treatment in the absence of wound healing peptides.
  • the wound healing peptides are administered orally, topically, or by parenteral means, including subcutaneous and intramuscular injection, implantation of sustained release depots, intravenous injection, intranasal administration, and the like.
  • the wound healing peptides are administered in an amount or dose that is pharmaceutically or therapeutically effective.
  • a pharmaceutically or therapeutically effective dose or amount refers to a dose or amount of wound healing peptides or a composition containing wound healing peptides sufficient to induce a desired biological result. That result can be alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • this dose or amount will be sufficient to stimulate or augment the epithelial and/or endothelial wound healing response and, thus, induce or potentiate wound healing.
  • wound healing peptides disclosed herein are provided in a variety of
  • compositions compatible with peptides can include one or more wound healing peptides, and one or more carriers or excipients.
  • Wound healing peptides may be administered as a pharmaceutical composition comprising one or more wound healing peptides in combination with one or more pharmaceutically acceptable carriers or excipients.
  • Such compositions may be aqueous solutions, emulsions, creams, ointments, suspensions, gels, liposomal suspensions, and the like. Suitable carriers
  • excipients include water, saline, Ringer's solution, dextrose solution, and solutions of ethanol, glucose, sucrose, dextran, mannose, mannitol, sorbitol, polyethylene glycol (PEG), phosphate, acetate, gelatin, collagen, CARBOPOL®, vegetable oils, and the like.
  • PEG polyethylene glycol
  • phosphate acetate
  • gelatin collagen
  • CARBOPOL® vegetable oils
  • One may additionally include suitable preservatives, stabilizers, antioxidants, antimicrobials, and buffering agents, for example, BHA, BHT, citric acid, ascorbic acid, tetracycline, and the like.
  • Cream or ointment bases useful in formulation include lanolin, SILVADENE®, AQUAPHOR®, and the like.
  • Topical formulations include aerosols, bandages and other wound dressings.
  • one may incorporate or encapsulate the wound healing peptides in a suitable polymer matrix or membrane, thus providing a sustained-release delivery device suitable for implantation near the site to be treated locally.
  • suitable devices for delivering or administering the compositions provided herein include indwelling catheters and devices such as the ALZET® minipump.
  • Ophthalmic preparations may be formulated using commercially available vehicles such as SORBI-CARE®,
  • NEODECADRON® may employ topical preparations such as that described in U.S. Pat. No. 5,124,155, incorporated herein by reference.
  • “Pharmaceutically acceptable salts” refer to the non-toxic alkali metal, alkaline earth metal, and ammonium salts commonly used in the pharmaceutical industry including the sodium, potassium, lithium, calcium, magnesium, barium, ammonium and protamine zinc salts, which are prepared by methods well known in the art.
  • the term also includes non-toxic acid addition salts, which are generally prepared by reacting the compounds provided herein with a suitable organic or inorganic acid.
  • Representative salts include the hydrochloride, hydrobromide, sulfate, bisulfate, acetate, oxalate, valerate, oleate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napsylate and the like.
  • pharmaceutically acceptable refers to compounds and compositions which may be administered to mammals without undue toxicity.
  • Exemplary pharmaceutically acceptable salts include mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and the like; and the salts of organic acids such as acetates, propionates, malonates, benzoates, and the like.
  • one or more wound healing peptides may be provided in a heat stable form, such as in a powdered or encapsulated formulation for delivery and use without the need for refrigeration.
  • a heat stable form such as in a powdered or encapsulated formulation for delivery and use without the need for refrigeration.
  • forms include solid forms, especially as a lyophilized powder.
  • Lyophilized formulations typically contain stabilizing and bulking agents, for example human serum albumin, sucrose, mannitol, and the like. A thorough discussion of pharmaceutically acceptable excipients is available in Remington's Pharmaceutical Sciences (17th edition, Mack Publishing Co., Easton, PA).
  • Example 1 Biochemical characterization of SANTYL® collagenase API and its extracellular matrix-derived peptide producing activities: Identification and Creation of innovative, Bioactive ECM-derived Wound Healing Peptides.
  • the active pharmaceutical ingredient (API) enzyme(s) present within SANTYL® collagenase Ointment were used to produce peptides from well-defined, bio- synthesized extracellular matrices derived from living, human epidermal and dermal cell cultures in vitro.
  • peptides which were produced by collagenase cleavage of synthesized endothelial or fibroblastic matrices, four peptides were "re-engineered". These re-engineered peptides are not naturally produced via collagenase-digestion; the collagenase- produced "parent" peptide(s) were re-engineered to optimize and maximize wound healing potential. These include peptides TSN9, TSN10, TSN18, TSN19, which possess amino acid sequence identity to, at least, two distinct collagenase-liberated peptides identified by mass spectrometry (see Figure 1, Table 1).
  • the peptides were synthesized at Tufts University Core Facility and their biological activity evaluated in a series of tests, including (i) ability to stimulate cell-specific proliferation, (ii) activation of angiogenesis and (iii) wound healing, in vitro and in vivo.
  • TSN Peptides 1-9 are derived from Human Dermal Endothelial Cell Extracellular Matrix.
  • TSN Peptides 10-19 are derived from Human Dermal Fibroblast Extracellular Matrix).
  • the procedure for producing extracellular matrix is from Herman and Castellot, Arteriosclerosis. 1987 Sep-Oct;7(5):463-9.
  • Table 1 SANTYL® coUagenase API-produced and Extracellular Matrix-derived Peptides
  • TSN12 11 aa ELADSPALEIG 12 protein N-terminal domain Combination of 11
  • Example 2 SANTYL® collagenase API-produced and extracellular matrix-derived peptides significantly stimulate the cellular responses to injury in vitro. Cell Proliferation, Post-Injury Migration and Angiogenesis.
  • SANTYL® collagenase API-derived bioactive wound healing peptide(s) we continue to perform a battery of pre-clinical tests and trials using the well-established models of injury and repair developed, here, at Tufts University School of Medicine and the Center for Innovations in Wound Healing Research. To these ends, we took advantage of the 2D and 3D injury/repair models developed to quantify cellular responses to injury. Outcomes of these studies have conclusively revealed that the newly-discovered peptides are able to promote cellular wound healing responses. As shown in Figure 2, several TSN peptides possess profound pro-proliferative properties when delivered to human cell cultures, including keratinocytes, endothelial cells and fibroblasts.
  • FIG. 2 shows that TSN1 and TSN2, as representative examples amongst other newly-identified and synthesized ECM-derived peptides, stimulate human dermally-derived microvascular endothelial cell growth in vitro.
  • TSN1 and TSN2 exceed the growth-promoting activity embodied in fibroblast growth factor 2 (FGF2), which is, perhaps, amongst the most mitogenic and angiogenesis inducer activities known.
  • FGF2 fibroblast growth factor 2
  • these bioactive peptides promote adult human keratinocyte proliferation in the 1-10 nM range, e.g. see Figure 3B, completely accounting for the keratinocyte growth-promoting activity present within PK SANTYL collagenase API (cf. Figure 3B, PK vs. TSN1, TSN2, TSN10). This is especially noteworthy since these peptides not only promote vascular endothelial growth but, adult human keratinocyte growth.
  • patent microvascular endothelial lined “tubes” can be produced in vitro when cells are either plated upon or are embedded within growth factor-reduced Matrigel.
  • ECM-derived and "re-engineered” peptides are able to stimulate wound healing angiogenesis, in addition to the microvascular endothelial growth promoting activity already demonstrated, population density matched cell numbers were plated in control or peptide-treated cultures and the angiogenic activities of the peptides quantified as a function of time in culture.
  • peptide- stimulated endothelial tubes are more numerous, of greater length, having more branch points then control treated endothelial cell cultures.
  • TSN2 which has angiogenesis-inducing activity also promotes keratinocyte migration in response to injury
  • these data suggest that the migration-enhancing activity embodied in this thrombospondin-1 domain may act upon keratinocytes and endothelial cells in the same manner or through the same molecular mechanism(s).
  • Example 3 SANTYL® collagenase API-produced and extracellular matrix-derived peptides significantly stimulate the cellular responses to injury and wound healing in vivo.
  • the peptides described herein which have significant migration-enhancing, growth- promoting and angiogenesis-inducing activity in vitro, similarly possess wound healing activity in vivo.
  • wound healing studies in vivo a model of impaired healing, cyclophosphamide-induced neutropenia, was used.
  • Full thickness excisional wounding of the cutaneous tissues located over the cranium was performed. While only one 8mm diameter full thickness excisional wound can be made per mouse, the means by which healing occurs is closely aligned with human cutaneous wound healing, i.e., via migration and proliferation vs. contraction (as is the case on the rodents' flanks).
  • animals were treated according to NIH guidelines for the care and well-being of laboratory animals, were injured under full anesthesia and then receive pain-alleviation, post-operatively.
  • test entities were coded so that the nature of the experiment was blinded to the investigator; and, each specimen was evaluated and scored blindly according to the wound healing system shown in Table 2, prior to unmasking the experimental code.
  • Table 2 modified wound scoring system. Tissues were collected as described herein and depicted in Figure 6, sectioned and stained with Haematoxylin and eosin. Scores were assigned to each wound by an investigator in a blind manner.
  • peptide-treated groups (and, in particular those treated with TSN6, which is comprised of a coiled domain contained within multimerin), were markedly stimulated to heal wounds compared to untreated controls or groups treated with collagenase, alone, or other peptides.
  • Newcomb PM Herman IM. Pericyte growth and contractile phenotype: modulation by endothelial- synthesized matrix and comparison with aortic smooth muscle. J Cell Physiol. 1993 May;155(2):385-93. PMID: 8482730.

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Abstract

La présente invention concerne des procédés et des compositions pour le traitement de plaies chez un sujet mammifère. Particulièrement, l'invention concerne de nouveaux polypeptides bioactifs qui activent la réparation et la régénération de tissus, notamment l'activation/stimulation de la cicatrisation de plaie et de la fermeture de plaie, et stimulent la motilité et/ou la prolifération des kératinocytes et des cellules endothéliales.
PCT/US2015/065181 2014-12-12 2015-12-11 Les peptides dérivés de la collagénase activent la régénération tissulaire et la cicatrisation des plaies WO2016094764A1 (fr)

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JP2017531329A JP2018502566A (ja) 2014-12-12 2015-12-11 コラゲナーゼ由来ペプチドは組織再生および創傷治癒を促進する。
US15/534,140 US10485846B2 (en) 2014-12-12 2015-12-11 Collagenase-derived peptides promote tissue regeneration and wound healing
EP15868322.7A EP3229821B1 (fr) 2014-12-12 2015-12-11 Les peptides dérivés de la collagénase activent la régénération tissulaire et la cicatrisation des plaies
AU2015360399A AU2015360399A1 (en) 2014-12-12 2015-12-11 Collagenase-derived peptides promote tissue regeneration and wound healing
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WO1992013887A1 (fr) * 1991-02-07 1992-08-20 The Victoria University Of Manchester Nouveaux peptides d'adhesion cellulaire
US20060051774A1 (en) * 2004-01-27 2006-03-09 Dvir Dahary Novel nucleotide and amino acid sequences, and assays and methods of use thereof for diagnosis of prostate cancer
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